S126: GEMTUZUMAB-BASED INDUCTION CHEMOTHERAPY COMBINED WITH MIDOSTAURIN FOR FLT3 MUTATED AML. RESULTS FROM THE NCRI AML19 “MIDOTARG” PILOT TRIAL
Authors: N. Russell, C. Wilhelm-Benartzi, J. Othman, R. Dillon, N. Potter, J. Jovanovic, A. Gilkes, L. M. Batten, J. Canham, E. L. Hinson, P. Kottaridis, J. Cavenagh, C. Arnold, M. Dennis, S. Knapper
Journal: HemaSphere (2022)

Background: Following the RATIFY study Midostaurin in combination with "7 + 3" like chemotherapy has become the standard of care for patients with newly diagnosed FLT3 mutated AML. The ALFA 0701 trial also suggested a benefit for Gemtuzumab Ozogamicin (GO) in FLT3 mutated AML however the combination of GO-based induction with Midostaurin has not been formally assessed. Aims: To assess the safety of midostaurin in combination with Gemtuzumab and intensive induction therapy and to assess impact of the combination on MRD kinetics Methods: The NCRI AML19 trial randomised patients to receive DA 3 + 10 (Daunorubicin 60mg/m2 on days 1,3,5 plus AraC 100mg/m2 bd on days 1-10) plus a single dose of GO 3mg/m2 on day 1 (DAGO1) or 2 doses (3mg/m2, maximum 5mg) on days 1 and 4 (DAGO2) plus 50mg bd of midostaurin (m) for 14 days following completion of chemotherapy. Eligibility included age 18-60 years with a FLT3-ITD or TKD mutation. Enhanced pharmacovigilance (PV) was performed for four weeks following the first induction course. Midostaurin was also given following second induction (DA 3 + 8 without GO) and 2 courses of HDAC consolidation and as maintenance for 12 cycles in non-transplanted patients. From November 2020 to November 2021, 77 patients were enrolled into the Midotarg pilot receiving DAGO1m (n=39) or DAGO2m (n=38). 59 had a FLT3 ITD and 22 a FLT3-TKD (and 4 had both). 59 patients have completed course 1 and are evaluable. RT-qPCR MRD monitoring for patients with an NPM1 mutation (n=48) was performed following each cycle of chemotherapy. A descriptive comparison is presented here of toxicity and MRD kinetics with FLT3 mutated patients receiving DAGO1 or DAGO2 without Midostaurin in the same trial. Results: Treatment compliance in course 1 was 88% for DAGO1m and 100% for DAGO2m. One patient did not receive any Midostaurin because of colitis during induction. Dose interruption for QTc prolongation occurred in 1 patient. A total of 17 SAEs (CTC grade 3 or greater) were reported (GO1, n=11, GO2 n= 6). Day 60 mortality was 0%. No cases of VOD were reported. Blood count recovery was not delayed. Time to neutrophil recovery to 1 x 109/L was 31 and 32 days with DAGO1m and DAGO2m compared to 31 and 32 days in DAGO1 and DAGO2 .. Time to platelet recovery to 100 x 109/L was 28 and 29 days with DAGO1m and DAGO2m respectively compared to 30 days in DAGO1 and DAGO2. Complete remission (CR plus CRi) was achieved in 51/59 (88%) evaluable patients who have completed induction with DAGOm. In 44 evaluable patients in remission with NPM1 mutation, 34 (74%) were MRD negative in the peripheral blood after course 2. This compares with 63% in 54 evaluable patients with DAGO only. Bone marrow NPM1 transcript levels after courses 1 to 4 were compared with FLT3 mutated patients receiving DAGO1 and DAGO2 without Midostaurin (Figure 1) with a higher proportion of patients becoming MRD negative from course 2 onwards and 81% being MRD negative after course 4. Image:Summary/Conclusion: The addition of midostaurin to DAGO using a single or fractionated dose of GO was well tolerated with no evidence of increased toxicity, high response rate and with encouraging clearance of NPM1 mutant transcripts. A randomised study of DAm versus DAGOm in FLT3 mutated AML is planned